Novel recognition site for l-quisqualate sensitizes neurons to depolarization by l-2-amino-4-phosphonobutanoate ( l-AP4)

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Brief exposure of rat hippocampal slices to l-quisqualate sensitizes pyramidal neurons to depolarization by l-2-amino-4-phosphonobutanoate ( l-AP4). We report here experiments designed to clarify the duration, pharmacology, mechanism, and pathway specificity of this ‘QUIS-effect’. The quisqualate-induced sensitization to l-AP4 decreases only 3-fold over a 4 h period. No compound besides quisqualate has been found to induce the QUIS-effect, including quisqualate analogues, potent excitatory amino acid agonists, l-glutamate, l-aspartate, and compounds known to stimulus second messenger systems in hippocampal slices. Of 43 compounds assayed here, only 5 are able to block the induction of the QUIS-effect. Although these blockers are also potent ligands at a chloride-dependent glutamate uptake site, the marked difference in rank ordering of compounds for QUIS-effect blockade and uptake site potency suggests that the QUIS-effect is not induced through this uptake site. The QUIS-effect can be induced in the CA1 region, the medial perforant path, and the lateral olfactory tract of the rat, and in the guinea pig CA1. It cannot be induced in the l-AP4-sensitive rat lateral perforant path (LPP), suggesting that the receptors for l-AP4 in the LPP may be distinct from those that are sensitized by quisqualate in the other pathways.